Tag Archives: Key Biscayne

What did Sequana really find at Tristan da Cunha?

The Tristan da Cunha asthma study  was leading to patent US6087485A. The patent describes

highly significant linkage in the genome scan (p=0.0001 for history of asthma and p=0.0009 for methacholine challenge) … at D11S907, a marker on the short arm of chromosome 11.

D11S907 or  AFM109YA1 is a microsatellite marker located at 11p13 in a gene known as EHF (ETS homologous factor).  There should be 2 genes in close proximity of the marker: ASTH1I and ASTH1J.

ASTH1I and ASTH1J were detected by exon trapping. ASTH1I exons detected a 2.8 kb mRNA expressed at high levels in trachea and prostate, and at lower levels in lung and kidney …
ASTH1J exons detected a 6.0 kb mRNA expressed at high levels in the trachea, prostate and pancreas and at lower levels in colon, small intestine, lung and stomach.

The sequences of  table 2 in the patent are sufficient now to locate ASTH1I and ASTH1J. Continue reading What did Sequana really find at Tristan da Cunha?

25 years Transatlantic Airway Conference 1997 on asthma genetics in Key Biscayne

The conference series started in 1986 while the 12th conference was organized by Jeff Drazen with local support of Adam Wanner.

 

Sponsored by Boehringer Ingelheim, the participant list is the WHO is WHO in pulmonary genetics at that time: Bleecker, Meyers, Woolcock, Weiss, Burrows, Postma, Kauffmann, Dizier, LeSouef, Blumenthal, Banks-Schlegel, Slutsky, Zamel, Ober, Bousquet, Vercelli, Barnes, Adcock, Dahlen, Pauwels, Lewitt, Aron, Martinez, Cookson, Moffatt, Rosenwasser, Liggett, Rich, Papadopoulos, Levitt, Holgate, Elston, Morton and Marsh. Many of them do not live any more [1,2,3,4,5], some have made big careers [1,2], others have been fallen somewhat into disgrace [1,2,3]  and many already retired. Continue reading 25 years Transatlantic Airway Conference 1997 on asthma genetics in Key Biscayne

How atopic dermatitis is linked to vitamin D and how IL33 splice variants associate to eosinophil numbers

(first published 12 Dec2020 and revised 10Dec2021)

We had a major discussion right before our 2010 paper where I argued that rare variants should have been included into our asthma/allergy/dermatitis GWAS. Ten years after there is now a nice paper using massive exome sequencing that finally includes them.

It seems that the respiratory tract isn’t so much influenced by rare gene variants but that there is a strong effect in  the immune system.

And there is another interesting fact.

…Surveying the contribution of rare variants to the genetic architecture of human disease through exome sequencing of 177,882 UK Biobank participants …if we look at the …. European population who are carriers of a filaggrin (FLG) PTV, we find those carriers have significantly higher risk for well-known associations, such as dermatitis  … and asthma … Concomitant increases in vitamin D levels suggest … increased sensitivity to ultraviolet B radiation.

So far, I have only assumed an asthma/allergy priming effect of oral vitamin D in the newborn gut. This paper now argues for an increased vitamin D sensitivity also in the skin of  FLG dermatitis patients which is interesting given the largely contradictory data of serum vitamin D and atopic dermatitis. Maybe dermatologists should focus their research more on skin and local vitamin D turnover?

 

-II-

 

The most prominent IL33 variant carried by over 2,300 people is splice acceptor 9-6250473-G-C followed by 600+ individuals with splice donor 9-6250600-G-T.

There are not too many carriers of this variant by the sheer amount of 177,882 participants. We nevertheless know already something about the seven IL33 splice variants since 2012.

Novel Splice Variants of IL-33: Differential Expression in Normal and Transformed Cells Journal of Investigative Dermatology (2012) 132, 2661–2664; doi:10.1038/jid.2012.180

with updates  in  2016

Gordon, Alternative splicing of interleukin-33 and type 2 inflammation in asthma, PNAS 2016

as well as in 2017

Fig 3A Smith et al. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma, PLoS Genetics 2017 – describes the splice site as NM_001199640:exon7:c.487-1G>C or rs146597587-C

 

So I did a sequence match to compare the new finding with these older publications.

own sequence match exon7 using data from dbSNP, UCSC GoldenPath and Uniprot – reference is hg19

 

Indeed, the 2017 paper already described rs146597587 which is probably identical to the splice acceptor 9-6250473-G-C in Astra UK Phewas (genome positions do not match – I used hg19 while I don’t know the Astra reference) . Astra says also c.613-1G>C while rs146597587 is just upfront of my codon 205 (3*205=615) whatever that means.

The Astra UK Phewas at least confirms the Iceland paper above

rs146597587-C associates with lower eosinophil counts (ß= -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids.

So it is basically a rediscovery meaning that we reached saturation.

How it is going, how it started – asthma genome wide scans

Here are the most recent GWAS data for asthma – not identical peaks but quite similar. How it is going 2021

 

PMC5901974

big.stats.ox.ac.uk

pheweb.sph.umich.edu

r2.finngen.fi

www.ebi.ac.uk

 

And here is how it started 1986

third linkage scan (my PhD thesis)

second  linkage scan (CSGA)

first linkage scan (Cookson)

More than 2 decades ago we found hits on chromosome 2, 6, 9, 12 (missing  chr17q21 where our marker coverage wasn’t probably good enough). It seems that this was the first identification of the IL33 region although IL33 could be described only 7 years later. Remarkably,  this result was possible with just 415  individuals instead of 500,000 individuals nowadays (see also the asthma genetics timeline).

Nature Genetics corrupted by 23andme

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Timeline asthma / allergy genetics

First Genetic Study
1923 AF. Coca.J Immunol 8:163-171

First Linkage Study (AB0 blood group)
1936. I. Zieve, Ann Hum Gen 7:4074, 163-178

First Molecular Study (HLA)
1973 D. Marsh, Science 179:4074, 691-3

Second Linkage Study (SLC14A1)
1985, H. Eiberg, Cytogenet Cell Genet 40: 622 -journal discontinued, no online archive-

Third Linkage Study (11q31)  – questionable results
1989 W. Cookson, Lancet 1:8650, 1292-5

First Modern Family Study
1992 S. Dold,  Arch Dis Child 67:8, 1018-22

First gene (Fc∈RI-β)
1993 A.J.Sandford,  The Lancet  341:8, 332-334

First true gene (IL4)
1994 D. Marsh, Science 264:5162, 1152-6

First Genomewide Linkage Scan
1996 S. Daniels, Nature 383:6597, 247-50

Transatlantic Airway Conference Key Biscayne FL
1997 N. Zamel (only reported later by Thompson  2003 and Duffy 2019)

Second Genomewide Linkage Scan
1997 CSGA  Nature Genetics 15:389-392

Third Genomewide Linkage Scan
1999 M. Wjst,  Genomics 58:1-8

First GWAS
2007 M. Moffatt, Nat Genet 15:389-392

Second GWAS
2008 C. Ober,  NEJM 358: 1682-91

then it is getting confusing